Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-23
2000-06-13
Fay, Zohreh
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514725, 514912, A61K 31435, A61K 3107
Patent
active
060750324
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to pharmacological uses of retinoids. More particularly, this invention relates to use of retinoids in treatment of ocular disorders.
2. Description of Related Art
The retinal pigment epithelium (RPE) forms a monolayer of cells beneath the sensory retina that is normally mitotically inactive except when it is participating in retinal wound repair, in which it plays a central role. When wound repair is complete, the RPE usually stops proliferating; failure to do so can result in blinding disorders such as proliferative vitreoretinopathy (PVR) and disciform scarring. For instance, after detachment of the sensory retina, the RPE changes in morphology and begins to proliferate. Multilayered colonies of dedifferentiated RPE cells are formed. Cells then begin to migrate into the subretinal space where they engulf rod outer segments. In some instances cells migrate onto the surface of the retina and form epiretinal membranes. These events have been implicated in the pathogenesis of proliferative vitreoretinopathy, severe scarring occurring in association with macular degeneration, and poor or delayed recovery of vision after retinal reattachment.
Age-related macular degeneration (AMD) is the major cause of blindness in patients over the age of 60 in the United States. Severe loss of vision in patients with AMD is usually due to the development of choroidal neovascularization (CNV). Laser treatment can ablate CNV and help to preserve vision in selected cases not involving the center of the retina; however, the treatment benefit is often transient due to the high rate of recurrent CNV (50% over 3 years and approximately 60% at 5 years) (Macular Photocoagulation Study Group, Arch. Ophthalmol. 204: 694-701, 1986). In addition, many patients who develop CNV are not good candidates for laser therapy because the CNV is too large for laser treatment, or the location cannot be determined so that the physician cannot accurately aim the laser.
Despite these important consequences, little is known about the stimuli involved in RPE dedifferentiation and loss of density-dependent growth control. However, it is known that cultured human RPE rapidly become depleted of retinoids when maintained in media supplemented with fetal bovine serum (FBS) (S. R. Das, et al., Biochem. J., 250:459, 1988). Retinoids have been implicated in cellular differentiation (S. Strickland, et al., Cell, 15:393-403, 1978; T. R. Brietman, et al., PNAS, 77:2936-2940, 1980; and are normally present in high levels in RPE in vivo. Retinoids play a prominent role in visual transduction and therefore their recycling is needed for normal visual function. This recycling occurs through an intimate relationship between the photoreceptors and the RPE. Disruption of this intimate relationship during retinal detachment prevents recycling of retinoids and may be one reason for outer segment degeneration and dedifferentiation of the RPE (P. A. Campochiaro, et al., Invest. Opthalmol. Vis. Sci., 32:65-72, 1991).
Incubation of cultured RPE cells with all-trans retinoic acid (RA) inhibits cell proliferation and promotes a morphologic appearance like RPE in situ (P. A. Campochiaro, et al., supra; J. W. Doyle, et al., Curr. Eye Res. 11:753-765, 1992). All-trans RA and other derivatives of vitamin A (generally referred to as retinoids) affect the growth and differentiation of many cell types (S. Strickland, et al., supra; T. R. Breitman, et al., Proc. Natl. Acad. Sci. USA, 7:2936-2940, 1980). Therefore, retinoic acid or a related molecule may be one of the signals that helps to maintain or re-establish quiescence of RPE and other cells that participate in PVR.
The biological effects of retinoids are mediated through nuclear receptors which are ligand-induced trans-acting factors that bind to DNA response elements, modulating the transcription of genes containing those response elements.
These receptors are divided into two major families, retinoic acid receptors (RARs) and retinoid X receptors (RXRs
REFERENCES:
patent: 5234926 (1993-08-01), Chandratna
Campochiaro Peter A.
Chandraratna Roshantha A.
de Juan, Jr. Eugene
Nagpal Sunil
Wheeler Larry A.
Allergan
Fay Zohreh
Johns Hopkins University School of Medicine
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